Single gene mutations cause approximately 1% of all cases of diabetes and up to 10% of cases diagnosed at less than 35 years of age. However, the vast majority of cases of monogenic diabetes are misdiagnosed as type 1 or type 2 diabetes. Here we propose to evaluate the consequences of a diagnosis of monogenic diabetes and to develop and validate new cost-effective methods to improve diagnosis and treatment. We and others have suggested that a precise genetic diagnosis of diabetes enables targeted therapy, leads to improved quality of life, and aids in diagnosis of diabetes in other family members including earlier diagnosis in children. Despite this, the overwhelming majority of patients with these forms of diabetes remain undiagnosed and most often inappropriately treated. Those with diabetes due to mutations in KCNJ11, ABCC8, HNF1A and HNF4A may be effectively managed with sulfonylurea therapy instead of suboptimal insulin injections, while individuals with GCK-related diabetes generally do not require drug treatment. However, the best treatment of several other forms of monogenic diabetes remains poorly understood. Furthermore, the variables predicting failure of monotherapy in sulfonylurea-responsive forms and the best choices for second-line agents is not known. Using a simulation model of diabetes costs and complications, we have demonstrated the potential cost-effectiveness of genetic testing for the diagnosis of neonatal diabetes and MODY. The development of targeted next-generation sequencing approaches that facilitate testing of the more than 40 genes known to cause monogenic diabetes will allow us to efficiently examine the true cost-effectiveness of genetic testing. With genetic testing for diabetes slowly becoming more readily available, the impact of testing results - positive, negative and inconclusive - have not been fully assessed. We propose to 1) Determine the efficiency of next-generation sequencing in monogenic diabetes and impact on the cost-effectiveness of genetic testing leading to targeted treatment and 2) Determine the impact of positive genetic testing results on treatment and quality of life while also assessing th impact of indeterminate results. The overall goal of this proposal is to determine the benefits of routine testing for monogenic forms of diabetes in appropriately selected individuals and promote the resulting improvements in treatment through guidance and support of patients, families and physicians.